Advances in the design of ITK inhibitors

Charrier, Jean-Damien; Knegtel, Ronald M.A.

doi:10.1517/17460441.2013.769520

Cited by 15 publications

(18 citation statements)

References 52 publications

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“…We are currently investigating rational treatment combinations between ITK inhibitors and standard treatments for metastatic melanoma in various preclinical melanoma models that may serve as the basis for future clinical trials in metastatic melanoma. Besides BI 10N, several other ITK inhibitors previously have been developed to target Th2 dominant autoimmune, inflammatory, and infectious diseases (48, 49). Notably, ibrutinib (IMBRUVICA, Pharmacyclics, Inc.), an irreversible inhibitor of BTK and ITK (50), has been granted approval by the U.S. Food and Drug Administration.…”

Section: Discussionmentioning

confidence: 99%

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Carson

Moschos

Edmiston

et al. 2015

Clinical Cancer Research

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Purpose Interleukin-2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared to nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. Experimental Design An ITK specific monoclonal antibody was used to probe sections from de-identified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by immunohistochemistry. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. Results ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacological inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0/G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten null/Braf V600E) melanomas. Conclusions We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility.

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Section: Discussionmentioning

confidence: 99%

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Carson

Moschos

Edmiston

et al. 2015

Clinical Cancer Research

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“…Although we could not perform a head-to-head comparison of both inhibitors, evaluations of the potency of such ITK targeting have to consider the effects of individual drug selectivities (5). The affinity of PRN694 to ITK is reported to be higher than for BMS-509744 (IC 50 values: 0.3 nM versus 15 nM) (5).…”

mentioning

confidence: 99%

Interleukin-2-inducible T-cell Kinase (ITK) Targeting by BMS-509744 Does Not Affect Cell Viability in T-cell Prolymphocytic Leukemia (T-PLL)

Dondorf

Schrader

Herling

2015

Journal of Biological Chemistry

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“…TEC kinases are dysregulated in several malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma and diffuse large B-cell lymphoma (DLBCL) [81][82][83].…”

Section: Tec Protein Kinasementioning

confidence: 99%

“…BMS-509744 is a selective ATP-competitive inhibitor of ITK with an IC 50 value of 19 nM (Table 1) [83]. The inhibitory effects of this TKI have not been well studied in malignancies; however, several studies have shown the inhibitory effects in inflammatory and infectious diseases [96,97].…”

Section: Bms-509744mentioning

confidence: 99%

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

Hojjat‐Farsangi

2015

Journal of Drug Targeting

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Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.

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Advances in the design of ITK inhibitors

Cited by 15 publications

References 52 publications

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Interleukin-2-inducible T-cell Kinase (ITK) Targeting by BMS-509744 Does Not Affect Cell Viability in T-cell Prolymphocytic Leukemia (T-PLL)

Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances

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